The overall aim of this project is to evaluate the feasibility of novel bisphosphonate conjugates as treatment for prostate cancer metastasis and tumor-induced bone pain. Current treatments including bisphosphonates are mainly palliative. Disadvantages such as low bioavailability, little or no proven clinical impact as adjuvant therapy, and moderate reduction of skeletal complications raise numerous pharmacoeconomic issues in bisphosphonate treatment and necessitate the development of more efficacious analogs. Our proprietary drug designs employ vitamin B6- and, nucleotide-bisphosphonate conjugates to address these limitations and offer potential improvements in efficacy and side-effect profiles. Our prior in vivo results in mouse models of metastatic breast cancer showed decreased tumor burden and incidence of bone metastases upon treatment with MBC compounds. In addition, restoration of bone mineral density loss and increased survival in a mouse model of multiple myeloma was demonstrated. We have shown that MBC bisphosphonate compounds have unique and distinct effects on osteoblasts in vitro. In this proposed work, our proprietary chemistry will be used to develop novel conjugates that include third generation bisphophonate scaffolds. The antiproliferative properties of these compounds will be tested in prostate cancer derived and human osteoblast cell lines; and their effects on osteoblast cell mineralization will be assessed. The most potent conjugates will be tested through a range of dose levels in a rat model of prostatic tumor induced bone pain. Successful development of bisphosphontate conjugates for the treatment of prostate cancer induced skeletal complications would address the currently unmet medical needs of the >200,000 new cases of prostate cancer anticipated every year in the US. Our novel bisphosphonate conjugates may not only be used as a therapy for the treatment of bone metastatises and its related pain, but may prove to be an effective prophylactic that prevents the appearance of bone metastases and their related skeletal complications. Thus, the development of these therapeutics may not only improve the quality of life for prostate cancer patients but may also prolong their lives. [unreadable] [unreadable] [unreadable]